Inhibition of Cytochrome P450 Activities by Sophora flavescens Extract and Its Prenylated Flavonoids in Human Liver Microsomes.

Daeun Yim,Dong Hyun Kim,Su-Jun Lee,Yumi Shin,Jae Gook Shin,Min Jung Kim

doi:10.1155/2019/2673769

Abstract

Sophora flavescens possesses several pharmacological properties and has been widely used for the treatment of diarrhea, inflammation, abscess, dysentery, and fever in East Asian countries. S. flavescens is a major source of prenylated flavonoids, such as sophoraflavone and kushenol. In this study, we examined the effects of S. flavescens extract and its prenylated flavonoids on cytochrome P450 (CYP) isoform activity in human liver microsomes. The extract inhibited CYP2C8, CYP2C9, CYP2C19, and CYP3A activities, with IC50 values of 1.42, 13.6, 19.1, and 50 µg/mL, respectively. CYP2B6 was only inhibited in human liver microsomes preincubated with the extract. CYP3A4 was more strongly inhibited by the extract in the presence of NADPH, suggesting that the extract may inhibit CYP2B6 and CYP3A4 via mechanism-based inactivation. Prenylated flavonoids also inhibited CYP isoforms with different selectivity and modes of action. Kushenol I, leachianone A, and sophoraflavone G inhibited CYP2B6, whereas kushenol C, kushenol I, kushenol M, leachianone A, and sophoraflavone G inhibited CYP3A4 via mechanism-based inhibition. Our results suggest that S. flavescens may contribute to herb–drug interactions when coadministered with drugs metabolized by CYP2B6, CYP2C8, CYP2C9, and CYP3A4.

Highlights

The dried roots of Sophora flavescens, a traditional Chinese medicine, have been widely used in Korea, Japan, and China for the treatment of solid tumors and inflammatory disease [1]
We demonstrated that S. flavescens extract reversibly inhibited the activities of CYP2C8, CYP2C9, and CYP2C19 whereas it inhibited CYP2B6 and CYP3A4 in a mechanismbased inactivation manner
Because prenylated flavonoids act as inhibitors of cytochrome P450 (CYP) isoforms [23], the CYP inhibitory potential of six prenylated flavonoids from S. flavescens was evaluated in human liver microsomes (Figure 1)

Summary

Introduction

The dried roots of Sophora flavescens, a traditional Chinese medicine, have been widely used in Korea, Japan, and China for the treatment of solid tumors and inflammatory disease [1]. S. flavescens exerts diverse pharmacological properties including antianaphylaxis, antimicrobial, immunoregulatory, and cardioprotective activities [2]. These therapeutic effects of S. flavescens may be derived from complex interactions among its various constituents. Phytochemical analysis revealed the presence of quinolizidine alkaloids and prenylated flavonoids in S. flavescens [3, 4]. These two chemicals have been shown to exert a wide spectrum of pharmacological effects, such as anti-inflammatory, antitumor, antimalarial, and antiviral effects [2, 5,6,7,8]. Herb–drug interactions may occur via modulation of hepatic and intestinal cytochrome P450

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